We wish to continue our study of a new paradigm for the selective functionalization of complex molecules. Our approach is predicated on the development of fundamental reactions of functional groups that are ubiquitous in bioactive agents. Importantly, bioactive analog generation by this approach spans multiple therapeutic areas, and categorizes these chemical studies as a quintessential ?General Medical Science.? The main emphasis of this proposal is the development of simple-to-make catalyst libraries that target functionalization through a vast array of reactions. These will include site-selective reactions of hydroxyl groups, amines, arene C-H bonds, olefins and ketones. In addition, we target a host of redox-active functional groups, as well as an array of C-C bond-forming reactions. Many of these processes have been developed in our laboratory, with our initial studies often focusing on enantioselective catalysis ? a field of great importance in its own right, with high significance for the synthesis of pharmaceuticals. Yet, our focus is increasingly on the study of highly complex molecular environments, wherein our enantioselective chemistry serves as a prelude to exploration of substrates for which stereoselectivity represents just a subset of the issues that need to be addressed. We have extensive preliminary results in a number of complex molecular frameworks, including those provided by some venerable natural products, such as erythromycin, vancomycin, teicoplanin and thiostrepton. We wish to continue these studies, but in addition we wish to expand them to analog generation in contexts presented by structures like oligomycin, rapamycin and the aminoglycoside antibiotics. All of these objectives will require the development of new catalysts and new reactions. Foci will include high value catalytic, site-selective deoxygenation chemistry, site- selective amine functionalization, site-selective C-H bond functionalization, site-selective redox reactions, and site-selective C-C, C-O and C-N bond formations ? all in complex molecular scaffolds. An important parallel effort in our group includes the development of catalysts for selective control over unusual stereochemical issues, such as atropisomerism, which is an area of growing concern in medicinal chemistry. These projects will expand as well, also as a prelude to mastery of this stereochemical issue in complex molecular environments. The significance of our overall goals may be in new catalysis principles, and in their application to the site-selective modification of complex, bioactive natural products. These investigations thus extend fundamental studies of enantioselectivity to the less well-studied arena of regioselectivity. These efforts will also set the stage for the site-selective chemical alteration of complex polypeptides, and maybe even proteins. Thus, we wish to expand greatly our studies of the selective derivatization of fascinating biologically active agents, with site-selective catalysts as the principal tool. In all cases, we will continue to assess new analogs for their biological properties, hoping to extend further the biological activities we have unveiled in recent years.
We wish to continue our development of a new paradigm for the selective synthesis of complex bioactive molecules. Progress in this field enables efficient syntheses of candidates for new medicines, and eventually of the new medicines themselves. A particular emphasis involves catalysis in complex molecular environments, which is a long-standing problem in medicinal chemistry.